• A Corrigendum to this article was published on 15 June 2011

This article has been updated


Microtubules have pivotal roles in fundamental cellular processes and are targets of antitubulin chemotherapeutics1. Microtubule-targeted agents such as Taxol and vincristine are prescribed widely for various malignancies, including ovarian and breast adenocarcinomas, non-small-cell lung cancer, leukaemias and lymphomas1. These agents arrest cells in mitosis and subsequently induce cell death through poorly defined mechanisms2. The strategies that resistant tumour cells use to evade death induced by antitubulin agents are also unclear2. Here we show that the pro-survival protein MCL1 (ref. 3) is a crucial regulator of apoptosis triggered by antitubulin chemotherapeutics. During mitotic arrest, MCL1 protein levels decline markedly, through a post-translational mechanism, potentiating cell death. Phosphorylation of MCL1 directs its interaction with the tumour-suppressor protein FBW7, which is the substrate-binding component of a ubiquitin ligase complex. The polyubiquitylation of MCL1 then targets it for proteasomal degradation. The degradation of MCL1 was blocked in patient-derived tumour cells that lacked FBW7 or had loss-of-function mutations in FBW7, conferring resistance to antitubulin agents and promoting chemotherapeutic-induced polyploidy. Additionally, primary tumour samples were enriched for FBW7 inactivation and elevated MCL1 levels, underscoring the prominent roles of these proteins in oncogenesis. Our findings suggest that profiling the FBW7 and MCL1 status of tumours, in terms of protein levels, messenger RNA levels and genetic status, could be useful to predict the response of patients to antitubulin chemotherapeutics.

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Change history

  • 09 March 2011

    Minor errors in the HTML and PDF were corrected on 09March 2011.

  • 21 November 2011

    Supplementary Fig. S21 contained a duplicated panel instead of the SB203580-treated cdc27 blot.


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We thank P. Ekert for FDM cell lines, J. Stinson for sequencing assistance, S. Johnson and C. Santos for assistance with obtaining patient samples, P. Haverty for bioinformatics analysis, C. Grimaldi for cloning assistance, J. Dynek for TaqMan advice, D. French for tumour analysis, C. Quan and J. Tom for peptide synthesis, I. Zilberleyb and the Baculovirus Expression Group for cloning and protein production, S. Charuvu for generating MCL1 point mutants, A. Bruce for graphics assistance, the Genentech Cancer Genome Project Team, Z. Modrusan, R. Soriano and the microarray lab for ovarian tumour data sets, K. Newton for editorial assistance, W. Wei for sharing unpublished results, and A. Eldridge, D. Kirkpatrick, D. Vucic, E. Varfolomeev, T. Goncharov, A. Cochran, O. Huang, A. Huang, Y. Pereg, A. Loktev, D. Phillips, J. Wu, M. van Delft, D. Eaton, E. Shaulian, T. Hunter, S. Cory, J. Adams, A. Strasser, R. Deshaies and G. Evan for discussions. Work in the Huang laboratory is supported by the National Health and Medical Research Council (program grant #461221, IRIISS grant #361646 and a fellowship to D.C.S.H.), the Leukemia and Lymphoma Society (SCOR 7413), the National Institutes of Health (grants CA043540 and CA80188), the Australian Cancer Research Foundation, and an Australian Research Council Australian Postdoctoral fellowship to T.O. We apologize to our colleagues whose primary work could not be cited owing to space constraints.

Author information

Author notes

    • Cynthia Lam
    •  & Toru Okamoto

    These authors contributed equally to this work.


  1. Department of Early Discovery Biochemistry, Genentech, South San Francisco, California 94080, USA

    • Ingrid E. Wertz
    • , Saritha Kusam
    • , Cynthia Lam
    • , Elizabeth Helgason
    • , James A. Ernst
    • , Wayne J. Fairbrother
    •  & Erin C. Dueber
  2. The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria 3052, Australia

    • Toru Okamoto
    •  & David C. S. Huang
  3. Department of Protein Chemistry, Genentech, South San Francisco, California 94080, USA

    • Wendy Sandoval
    • , James A. Ernst
    •  & Jennie R. Lill
  4. Department of Research Oncology, Genentech, South San Francisco, California 94080, USA

    • Daniel J. Anderson
    • , Mike Eby
    • , Lisa D. Belmont
    • , Peter K. Jackson
    • , Mary J. C. Ludlam
    • , Kevin G. Leong
    •  & Heather Maecker
  5. Department of Bioinformatics, Genentech, South San Francisco, California 94080, USA

    • Jinfeng Liu
    •  & Joshua S. Kaminker
  6. Department of Physiological Chemistry, Genentech, South San Francisco, California 94080, USA

    • Karen M. O’Rourke
    •  & Vishva M. Dixit
  7. Department of Molecular Biology, Genentech, South San Francisco, California 94080, USA

    • Kanan Pujara
    •  & Somasekar Seshagiri
  8. Department of Biochemical Pharmacology, Genentech, South San Francisco, California 94080, USA

    • Pawan Bir Kohli
    •  & Adam R. Johnson
  9. Department of Structural Biology, Abbott Laboratories, Abbott Park, Illinois 60064, USA

    • Mark L. Chiu
  10. Department of Medical Biology, University of Melbourne, Parkville, Victoria 3010, Australia

    • David C. S. Huang


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I.E.W., S.K., T.O., J.A.E., P.B.K., A.R.J., C.L., E.C.D., E.H., H.M. and K.G.L. designed and performed in vitro, cell-based and in vivo experiments. D.J.A. and M.J.C.L. designed and performed microscopy experiments. S.K., C.L., K.M.O., M.L.C. and M.E. made constructs. J.L. and J.K. performed bioinformatics analysis, K.P. and S.S. provided sequencing analysis. W.S. and J.R.L. designed and performed mass spectrometry experiments. I.E.W., S.K., C.L., T.O., W.S., D.J.A., M.J.C.L., K.G.L., E.C.D., H.M. and V.M.D. prepared the manuscript and figures. W.S., L.D.B., P.K.J., W.J.F., D.J.A., P.B.K., A.R.J., M.J.C.L., H.M., D.C.S.H. and I.E.W. contributed to the study design and data analysis.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Ingrid E. Wertz.

Supplementary information

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  1. 1.

    Supplementary Information

    The file contains Supplementary Figures 1-39 with legends, Supplementary Methods, additional references and Supplementary Tables 1-2.

  2. 2.

    Supplementary Figure

    This file contains a corrected version of Supplementary Figure S21 and legend. This file was uploaded on 21 November 2011.

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